ABSTRACT
Background: Interleukin-6 (IL-6) is elevated in patients with active polymyalgia rheumatica (PMR) and is associated with disease activity, relapse and severity. Clinical trials with IL-6 receptor (IL-6R) inhibitors in PMR showed higher remission rates and reduced glucocorticoid (GC) use vs GC alone.1-4 Objectives: The SAPHYR study (NCT03600818) assessed the efficacy and safety of sarilumab (SAR), a fully human anti IL-6Rα monoclonal antibody, with a 14 week (wk) GC taper in patients with steroid resistant active PMR who fared on ≥7.5 mg/day prednisone or equivalent. Methods: Patients were randomized (1:1) to 52 wks of treatment with SAR 200 mg every 2 wks (Q2W) + 14 wk GC tapered regimen (SAR arm) OR placebo Q2W + 52 wk GC tapered regimen (comparator arm). The primary endpoint was the proportion of patients achieving sustained remission at wk 52, defned as disease remission by wk 12, absence of disease fare, CRP normalization from wks 12 to 52 and adherence to the per protocol GC taper from wks 12 to 52. Results: The study was terminated early due to protracted recruitment timelines during the COVID-19 pandemic, resulting in 118 of the intended 280 patients recruited between Oct 2018 and Jul 2020, and 117 were treated (SAR n=59, comparator n=58). The demographics were balanced;patients were primarily female, Caucasian, and a median age of ~70 years (Table 1). Overall, 78 patients completed the treatment (SAR n=42;comparator n=36). Primary reasons for treatment discontinuation were adverse events (AEs;SAR n=7, comparator n=4) and lack of efficacy (SAR n=4, comparator n=9). Sustained remission rate was signifcantly higher in the SAR arm vs the comparator arm (28.3% vs 10.3%;P=0.0193). Results of a sensitivity analysis excluding CRP from the sustained remission defnition was consistent with the primary analysis (31.7% vs 13.8%;P=0.0280). All sustained remission components favored SAR (Figure 1). Patients in the SAR arm were 44% less likely to have a fare after achieving clinical remission vs the comparator arm (16.7% vs 29.3%;HR 0.56;95% CI 0.35-0.90;P=0.0158). The comparator arm required more additional GCs vs the SAR arm, mainly due to PMR fare (median difference in actual and expected cumulative dose 199.5 mg vs 0.0 mg;P=0.0189). The cumulative GC toxicity index scores numerically favored SAR but the difference was not statistically signifcant. PMR activity scores improved in the SAR arm vs the comparator arm (LS mean-15.57 vs-10.27, nominal P=0.0002). Patient reported outcomes (eg, physical and mental health component scores, disability index, etc) favored SAR (Figure 1). Incidence of treatment-emergent AEs (TEAEs) was numerically higher in the SAR arm vs the comparator arm (94.9% vs 84.5%) and included neutropenia (15.3%) and arthralgia (15.3%) in the SAR arm, and insomnia (15.5%) in the comparator arm. Conversely, the frequency of serious AEs was higher in the comparator arm vs the SAR arm (20.7% vs 13.6%). No deaths were reported. Conclusion: SAR + 14 wk GC taper demonstrated signifcant efficacy vs the comparator arm in steroid refractory PMR patients, including clinically meaningful improvement in quality of life. Safety was consistent with the known safety profile of SAR.
ABSTRACT
Background: Low-dose glucocorticoid (GC) therapy is widely used in RA but the true balance of beneft and harm is still unknown. Objectives: We studied the effects of prednisolone (5 mg/day, 2 years) in RA patients aged 65+, requiring adjustment of antirheumatic therapy (DAS28≥2.60). Methods: Pragmatic double-blind placebo-controlled randomized trial;all co-treatments and changes therein were allowed during the trial except longterm open label GC;Ca/D supplementation was advised in all patients. Minimal exclusion criteria were tailored to seniors. Harm outcome: the number of patients with ≥1 serious adverse event (SAE), or ≥1 'other adverse event of special interest' (other AESI). Other AESI comprised any AE (except worsening of RA) causing study discontinuation, and GC-specifc events (Table 1). Beneft outcomes: improvement in disease activity (DAS28) and joint damage progression (Sharp/van der Heijde). Longitudinal mixed models analyzed the data. Given prior knowledge we report one-sided 95% confdence limit (95%CL) and statistical tests, performed only for the main outcomes. Results: We randomized 451 RA patients in 7 EU countries, 449 received the intervention;of these 63% prednisolone vs 61% placebo patients completed 2 years of follow up. Discontinuations were similar in both groups: for AE (14%) and active disease (4%);the remainder mostly for 'trial fatigue' and covid-related access issues (20%). Mean time on study drug was 19 (SD 8) months. 70% of patients were female, mean age was 72 (max 88) years, RA duration 11 years;67% were RF+, 56% ACPA+, 96% had joint damage on radiographs: mean score 20, median 8. Mean DAS28 was 4.5. Most patients (79%) were on current DMARD treatment, including 14% on biologics;47% had previously used GC, 14% changed DMARD therapy at baseline. Patients had mean 2.1 active comorbidities, and used median 7 drugs. Beneft: Disease activity rapidly declined to stabilize after 1 year (Figure 1), and was lower on prednisolone (adjusted mean difference in DAS28 over 2 years: 0.37, 95%CL 0.23, p<0.0001). The contrast in early (3-month) response was larger in 331 patients adherent to protocol on stable treatment: mean difference in DAS28 0.62 (95%CL 0.44), more responders on prednisolone (Figure 1). Sig-nifcant time-treatment interaction in secondary analyses suggested a decrease in contrast after the frst year, most likely caused by signifcantly more changes in DMARD treatment on placebo. Joint damage progression over 2 years was signifcantly lower on prednisolone: mean 0.6 (SD 1.9) v 1.8 (6.4) score points on placebo, difference 1.2 (95%CL 0.2, p=0.02). Harm: 60% prednisolone vs 49% placebo patients experienced the harm outcome: adjusted RR 1.24, 95%CL 1.04, p=0.02;number needed to harm 9.5 (Table 1). During the study 1 vs 2 patients died, and 3 vs 0 died within 5 months of discontinuation. Per 100 patient-years, AE totaled 278 in prednisolone vs 206 in placebo patients, and the difference was most marked for infections (Table 1);these were mostly mild or moderately severe. Other GC-specifc AESI were rare without relevant differences. Conclusion: Add-on low dose prednisolone has benefcial long-term effects on disease activity and damage progression in senior RA patients on standard treatment. The tradeoff is a 24% increase in patients with mostly mild to moderate AE, suggesting a favorable balance of beneft and harm.